Phytonadione compositions and related methods

ABSTRACT

Stable Phytonadione compositions for parenteral administration are provided which comprise (E) isomer of phytonadione at or greater than 97% w/w as the active ingredient, and is substantially free of (Z) isomer. Said compositions are stable, sterile, and particulate-free. Further, said compositions reduce or avoid allergic reactions to benzyl alcohol and polysorbate. In some aspects, the compositions are free or substantially free of benzyl alcohol and/or reduced amounts of polysorbate. Methods of manufacture and methods of administration also provided.

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 15/054,797, filed Feb. 26, 2016, which claimspriority to U.S. Provisional Patent Application Ser. No. 62/121,869,filed Feb. 27, 2015, the disclosures of which are herein incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to Phytonadione compositions and relatedmethods. Accordingly, the present invention concerns the fields ofpharmacy, medicine, and chemistry.

BACKGROUND

Phytonadione has been in use for several years in the United States andother countries. Phytonadione for parenteral administration has beenknown. Such compositions are administered to a significant number ofneonatal subjects and adults. Following is a description of one suchcomposition:

Phytonadione is 2-methyl-3-phytyl-1, 4-naphthoquinone. Its empiricalformula is C₃₁H₄₆O₂ and its structural formula is:

-   -   Vitamin K1 Injection (Phytonadione Injectable Emulsion, USP) of        Hospira is a yellow, sterile, nonpyrogenic aqueous dispersion        available for injection by the intravenous, intramuscular and        subcutaneous routes. Each milliliter contains phytonadione 2 or        10 mg, polyoxyethylated fatty acid derivative 70 mg, dextrose,        hydrous 37.5 mg in water for injection; benzyl alcohol 9 mg        added as preservative. May contain hydrochloric acid for pH        adjustment. pH is 6.3 (5.0 to 7.0). Phytonadione is oxygen        sensitive.

Another composition marketed by International Medicines company isdescribed as follows:

-   -   Phytonadione Injectable Emulsion, USP, is a yellow, sterile,        aqueous colloidal solution of vitamin K1, with a pH of 3.5 to        7.0. It is available for injection by the intravenous,        intramuscular, and subcutaneous route.    -   Each 0.5 mL contains 1 mg phytonadione (Vitamin K1), 10 mg        polysorbate 80, 10.4 mg propylene glycol, 0.17 mg sodium acetate        anhydrous, and 0.00002 mL glacial acetic acid. Additional        glacial acetic acid or sodium acetate anhydrous may have been        added to adjust pH to meet USP limits of 3.5 to 7.0. The air        above the liquid in the individual containers has been displaced        by flushing with nitrogen during the filling operation.

Both these compositions are known to cause serious adverse events suchas anaphylactic reactions. One of the currently marketed products hasthe following black box warning in its product labeling:

-   -   Severe reactions, including fatalities, have occurred during and        immediately after INTRAVENOUS injection of phytonadione, even        when precautions have been taken to dilute the phytonadione and        to avoid rapid infusion. Severe reactions, including fatalities,        have also been reported following INTRAMUSCULAR administration.        Typically these severe reactions have resembled hypersensitivity        or anaphylaxis, including shock and cardiac and/or respiratory        arrest. Some patients have exhibited these severe reactions on        receiving phytonadione for the first time. Therefore the        INTRAVENOUS and INTRAMUSCULAR routes should be restricted to        those situations where the subcutaneous route is not feasible        and the serious risk involved is considered justified.

It is unclear whether the anaphylactic reaction is caused by the drugitself, or one or more of the excipients, or their combination. Forexample, polysorbate, polyethoxylated fatty acids are known to havecaused adverse events. Benzyl alcohol and propylene glycol are known tobe toxic to pediatric patients. Despite the fact that phytonadione hasbeen on the market at least since 1983, there have been no productimprovements in an attempt to reduce the adverse events. This effort iscomplicated by the fact that phytonadione is oxygen-sensitive, and isinsoluble in water. Thus, formulation and process-related issues becomevery significant. There is a need to provide alternate formulations ofphytonadione to alleviate some potentially dangerous adverse events.Without wishing to be bound to any theory or mechanism of action, suchformulations are presented herein.

SUMMARY OF THE INVENTION

In some embodiments, provided herein is a stable sterile phytonadioneparenteral composition that comprises predominantly (E) isomer ofPhytonadione as the active principle, wherein the (E) isomer is presentat a concentration of from about 0.1 mg/ml to 20 mg/ml, the (Z) isomeris present at less than 3% w/w; preferably, less than 2% w/w or lessthan 1% w/w; or preferably, less than 0.5% w/w. In one aspect, thecomposition is completely free of a preservative such as benzyl alcohol.Benzyl alcohol quantitation in a pharmaceutical formulation is known inthe art. See for example, USP <51>(“Preservative Effectiveness Test, USP37-NF-32.”), which is incorporated by reference herein. In someembodiments, the composition is provided in a prefilled syringe or in avial.

For example, in some embodiments, provided herein are compositionscomprising phytonadione in its (E) isomer form that is substantiallyfree of its (Z) isomer. In some embodiments, the composition is providedin aqueous form. In some embodiments, the composition isparticulate-matter-free. In some embodiments, the composition issterile.

In some embodiments, the composition is configured to be injectable intoa mammal. In some embodiments, the composition is one or more or all ofstable, injectable, sterile, particulate-matter-free, and aqueous. Insome embodiments, the phytonadione is at a concentration of from about100 ug/ml. to about 20 mg/ml. In some embodiments, the compositionfurther comprises a pH adjuster. In some embodiments, the compositionhas a pH of from about 3.5 to about 8.0. In some embodiments, the (Z)isomer is present from about 0.5% to less than or equal to about 3% w/wof the (E) isomer. In some embodiments, the composition is free ofbenzyl alcohol. In some embodiments, the composition is free of orsubstantially free of cremophor and/or propylene glycol. In someembodiments, the composition comprises less than 20 mg/ml ofpolysorbate. In some embodiments, the composition is provided in acontainer suitable for storage, shipment, and/or use of the compositionin medical context. For example, in some embodiments, the composition isprovided in a non-reacting glass or non-reacting polymeric containerselected from a vial container or a pre-filled syringe container. Insome embodiments, the container is made of polyethylene or polypropyleneor a combination thereof. In some embodiments, an epoxide derivative ofthe (E) isomer of phytonadione is present at less than 4% w/w of the (E)isomer.

Further provided herein are uses of any of the above compositions orother compositions described herein. For example, in some embodiments,provided herein are uses for the treatment or prevention of a disease orcondition.

In some embodiments, provided herein are methods of administering any ofthe above compositions or other compositions described herein to amammal (e.g., a human). In some embodiments, the method comprises amethod of reducing the potential for anaphylactic reaction associatedwith phytonadione administration comprising: administering a compositioncomprising Phytonadione in its (E) isomer form that is substantiallyfree of its (Z) isomer, at a concentration of from about 0.1 mg/ml toabout 20 mg/ml; and optionally a pH adjuster, wherein the compositionhas a pH of from about 3.5 to about 8.0, wherein said (Z) isomer ispresent at about 3% w/w or less of the (E) isomer; and wherein saidcomposition is free of benzyl alcohol and a polysorbate at aconcentration of less than about 20 mg/ml. In some embodiments, thecomposition is administered from a vial or a pre-filled syringe whereinthe vial or pre-filled syringe is selected from a non-reacting glass orpolymeric material.

DETAILED DESCRIPTION

It is to be understood that this invention is not limited to theparticular structures, process steps, or materials disclosed herein, butis extended to equivalents thereof as would be recognized by thoseordinarily skilled in the relevant arts. It should also be understoodthat terminology employed herein is used for the purpose of describingparticular embodiments only and is not intended to be limiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a container” includes one or more of such containers andreference to “the agent” includes reference to one or more of suchagents. In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

As used herein, “Phytonadione” refers to a synthetic molecule describedabove. The (E) and (Z) isomer structures are known in the art. Under nocircumstances, Phytonadione as used herein does not encompasssynthetically radioisotope-labeled molecule (i.e., molecules thatcontain added radioisotopes beyond any that may be naturally present ina population of molecules)

As used herein, “subject” refers to a mammal. Examples of subjectsinclude humans, and may also include other animals such as horses, pigs,cattle, dogs, cats, rabbits, and aquatic mammals.

As used herein, the term “particulate-matter-free” or its grammaticalequivalents refer to the state in which the composition meets the USPrequirements for particulate matter in parenteral solutions oremulsions. See for example, USP XXXII, Chapter 788. One of skill in theart understands and knows how to assess whether a given compositionmeets USP particulate matter requirements.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 2 to about 50” should beinterpreted to include not only the explicitly recited values of 2 to50, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, 4, 5, 10, 14, 15, 20, 23, 25, 30, 35, 38, 40, 44,45, 48 and sub-ranges such as from 2-3, from 2-4, from 5-10, from 5-20,from 5-25, from 5-30, from 5-35, from 5-40, from 5-50, from 2-10, from2-20, from 2-30, from 2-40, fro. 2-50, from 10-15, from 10-20, from10-30, from 10-40, from 10-50, from 20-30, from 20-25, from 20-40, from20-50, etc. This same principle applies to ranges reciting only onenumerical value as a minimum or a maximum. Furthermore, such aninterpretation should apply regardless of the breadth of the range orthe characteristics being described. In some aspects, the term “about”may refer to +/−10% of a recited value, depending on the context as iscustomary in the art.

As noted in the Background section, current phytonadione formulationscarry several adverse events. A careful review was undertaken by presentinventors in an attempt to minimize some of the adverse events. Itincluded evaluation of the drug substance, its impurity profile, theexcipients, composition of parenteral phytonadione formulations, and themanufacturing process of phytonadione compositions. In that attempt, ithas been discovered that the formulation, the drug substance, and themanufacturing process, all could be improved.

First, with respect to the drug substance: Phytonadione may exist as amixture of two isomers, known as (E) and (Z) isomers. The precise ratioof these isomers in a given drug product composition is unknown. Somecommercial preparations may contain up to 20% of the cis (Z) isomer. Seefor example, Budavari, S. (ed.). The Merck Index—Encyclopedia ofChemicals, Drugs and Biologicals. Rahway, N.J.: Merck and Co., Inc.,1989., p. 1580. Commercially available phylloquinone (phytonadione)isprepared synthetically and may contain not only2′,3′-trans-phylloquinone (not less than 75%), but also2′,3′-cis-phylloquinone (up to 21% as per USP XXXII).

One complication is that the relative pharmacologic activity of the twoisomers is not precisely known. However, it is generally known that the(E) isomer is presumed to possess majority of or most of the activity ofthe Phytonadione composition. There are conflicting reports as to theactivity of the (Z) isomer. There has been no known phytonadione drugproduct composition that is substantially free of the (Z) isomer.Another impurity associated with phytonadione products is the epoxidederivative of each of the (Z) and (E) isomers. Thetrans-epoxyphylloquinone is suspected at about 4.0 percent. It has beendetermined herein that phytonadione compositions that containsubstantially isomerically pure (E) isomer of phytonadione areadvantageous. In one aspect, the (E) isomer comprises from about 95% toabout 99.9% of the active substance; in another aspect, the (E) isomeris from about 98% to 99.5%; in another aspect, the (E) isomer is from99% to 99.95%.

By increasing the isomeric purity of the drug substance, the totalcontent of the drug substance in the drug product has been reduced. Forexample, the drug substance of the drug product is now an (E)-isomerthat is present at from about 100 ug/ml to about 20 mg/ml. In someaspects, the (E) isomers from about 500 ug/ml to about 10 mg/ml, whilesimultaneously, the (Z) isomer in the composition is less than about 3%.One or methods to determine the (Z) isomer levels are known in the art.See for example, USP XXXVII phytonadione monograph, which isincorporated by reference.

Isomerically pure (E)-isomer composition may be prepared, for example bysolvent extraction, partition chromatography, distillation, and columnchromatography, or a combination thereof.

One or more methods to determine the (E) isomer levels for assaypurposes are known in the art. See for example, USP XXXVII phytonadionemonograph, which is incorporated by reference.

With respect to excipients: The International Medicines formulationcontains 20 mg/ml of polysorbate 80 and 20.8 mg/ml of propylene glycol.Polysorbate 80 is suspected to be causing anaphylactic reactions.Propylene glycol is considered not desirable in pediatric formulations.On the other hand, the formulation by Hospira contains polyoxyethylatedfatty acid derivative as a solubilizer and benzyl alcohol as apreservative. Polyoxyethylated fatty acid derivatives are suspected ofcausing anaphylactic reactions while also causing neurological andnephrological toxicities. Benzyl alcohol is recommended to be removedfrom pediatric patient formulations.

However, finding a substitute solubilizer is difficult due to the highlyinsoluble nature of phytonadione in water and many other commonly usedsolvents. After much work, it has been determined that polysorbateconcentration in the formulation can be reduced. For example, in certaincases, the polysorbate (which can be either Polysorbate 80 orPolysorbate 20, or other versions and mixtures thereof) in thecomposition is reduced to the extent that the polysorbate:(E) isomer ofphytonadione is less than 1:10; in some aspects, the ratio is less than1:9; or less than 1:8; or less than 1:7; or less than 1:6; or less than1:5; or less than 1:4; or less than 1:3; or less than 1:2; or less than1:1. In some aspects, the total polysorbate in the composition is lessthan about 70 mg/ml; or less than about 60 mg/ml; or less than about 50mg/ml; or less than about 40 mg/ml; or less than about 30 mg/ml; or lessthan about 20 mg/ml; or less than about 10 mg/ml; or less than about5mg/ml; or less than about 4 g/ml; or less than about 3 mg/ml; or lessthan about 2 mg/ml. In some cases, the polysorbate is at least 0.1mg/ml. Any composition with polysorbate concentration in the rangesstated in the previous sentences is within the scope of this invention.Thus, in many cases, a 20-40% reduction, or even 50-60%, or 70-80%, oreven up to 90% reduction is achieved in that excipient. Thus, oneunexpected advantage of reducing the total concentration of the drugsubstance is the ability to reduce the concentrations of thesolubilizing agents that are considered to be undesirable.

With respect to the manufacturing process, the following considerationsapply. Phytonadione is known to be oxygen-sensitive and light-sensitive.In some embodiments, provided herein are compositions that have in someaspects higher than previously known (E) isomer concentrations.Therefore, extra care should be taken to at least meet a specificationof less than 4%, but preferably, the (E) epoxide should be less than 3%,or less than 2%, or less than 0.5%. One difficulty is that thephytonadione compositions are preferably sterilized using heat. In thatcase, the probability of raising the (E)-epoxide levels is high.

Therefore, in some embodiments, to reduce the probability of increasingimpurities in the formulations, the oxygen in the container containingthe phytonadione composition is removed by way of replacement withnitrogen or argon or another inert gas. The replacement is done usingtraditional methods such as blowing with an inert gas and then sealingthe container. Alternatively, the phytonadione containers are firstevacuated and then filled with an inert gas, and then sealed. In oneaspect, the phytonadione containers are subjected to temperatures lessthan 2-8° C., or in some aspects minus 10° C. or less, or in someaspects minus 20° C. or less, or in some aspects minus 30° C. or less,and then evacuated, and then sealed, or alternatively, filled with aninert gas after evacuation, and then sealed. The compositions contain insome aspects less than 3% of the total impurities.

Phytonadione parenteral compositions are provided that comprise, consistof, or consist essentially of an isomerically pure drug substance,namely a drug substance that is greater than about 97%, or greater thanabout 98%, or greater than about 99% of the (E) isomer of Phytonadione,but in all cases contain less than 100% of the (E) isomer. In oneaspect, the composition comprises (E)-isomer of Phytonadione about 98%w/w, and a pharmaceutically acceptable carrier suitable for parenteraladministration. In one aspect, the composition comprises from about 100ug/mL to about 20 mg/mL of Phytonadione as its (E) isomer, and comprisesonly about 3.0% to about 0.5% of its (Z) isomer. The carrier mayinclude: a tonicity agent in sufficient concentration to make thecomposition isotonic. Examples of tonicity agents include, but notlimited to, sodium chloride, mannitol, sorbitol, dextrose, or organicsolvents such as ethanol, glycerin, sorbitol, etc., or a combinationthereof. The carrier may optionally include a pH adjustor or a bufferingagent. Some examples of such agents include: sodium hydroxide,hydrochloric acid, citrate, acetate, tartrate, and phosphatebuffers/buffering agents. In one aspect, the composition has a pH offrom about 3.5 to about 8.

In one embodiment, a Phytonadione composition that is ready toadminister to the patient is provided. In another embodiment thePhytonadione composition is injected intravenously, intramuscularly, orsubcutaneously both in pediatric and adult patients. In someembodiments, the composition is provided to the subject by slowinfusion. In one aspect, a Phytonadione ready-to-administer injectablecomposition that is sterilized using steam or super-heated water isprovided. In yet another aspect, an aqueous Phytonadione ready toadminister parenteral composition that is prepared by aseptic filtrationsterilization. The present ready to use Phytonadione injectablecomposition could be terminally sterilized and commercially produced inlarge quantities for commercial distribution. Terminal sterilization canbe accomplished in a suitable sterilizer employing steam, superheatedwater, or a combination thereof (generally known as heat sterilization).The appropriate sterilization conditions can be determined based on thenumber of units and the size of the units to be sterilized. In oneaspect, sterilization is conducted in an air over-pressure typesterilizer or steam sterilizer or water cascade type sterilizercommercially available. Exemplary time and temperature levels requiredfor adequate sterilization is to achieve and maintain a temperature ofabout 121 degrees C. for from about 7-8 minutes to about 30 minutes ormore as needed. Rotisserie autoclave/shaking of vials immediately afterremoving from the autoclave.

It should be recognized that even though the current compositions areterminally sterilizable, under certain conditions, the compositions maybe sterilized aseptically. Such aseptic sterilization may includefiltration or radiation methods, which are well-known in the art.

In one aspect, the compositions are not isotonic. For example,compositions for subcutaneous administration may not need to beisotonic. In such cases, the compositions may or may not include atonicity agent. Such compositions are also within the scope of thisinvention. When needed, the present formulations include a tonicityagent. Suitable tonicity agents may be selected from a number oftonicity agents. Exemplary agents include without limitation: sodiumchloride, mannitol, sorbitol, dextrose, or organic solvents such asethanol, glycerin, sorbitol, etc., or a combination thereof, or theirequivalents. One of skill in the art is aware of making compositionsisotonic using a tonicity agent such as sodium chloride or dextrose ortheir equivalents. Examples of such equivalents include but not limitedto mannitol, sorbitol, and glycerin. See for example, Remington: TheScience and Practice of Pharmacy, 19^(th) Ed., 1995, 613-27. In oneembodiment, an isotonic solution can have an osmotic pressure of about250-350 mOsmol/Kg.

In some embodiments, the pH of the compositions may be unadjusted, oradjusted so that the composition may have a pH ranging from about 3.5 toabout 8.0. When the pH is to be adjusted, a suitable pH adjuster such assodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid,or organic pH adjustors such as cysteine, lysine, acetic acid, citricacid, may be used.

An appropriate concentration of acid or base may be from about 0.1M to1M or more. The compositions may be supplied in a glass vial, preferablyamber vial (for example, Type II) or pre-filled syringes or in a plasticcontainer made from polyethylene, polypropylene or a combinationthereof. The container may range in size from about 0.5 ml to 10 ml. Inanother aspect, one or all of the compositions of the invention aresterile, substantially particulate-matter-free. In another aspect, oneor all of the compositions are stable. For example, in addition to beingparticulate-matter-free, the compositions retain at least 95% of theoriginal amount of Phytonadione after having been stored at 60° C. forone week. Additionally provided is a container including a terminallysterilized stable ready to administer Phytonadione injectablecomposition comprising, consisting of, or consisting essentially of a(E)-Phytonadione, at a concentration of about 100 ug/ml to 20 mg/ml,either sodium chloride, dextrose, or mannitol as a tonicity agent at aconcentration sufficient make the composition isotonic, and a pHadjuster or a buffer to provide the composition a pH of from about 3.5to about 8.0.

The phytonadione composition is prepared by emulsifying techniques knownin the art. For example, homogenizers are used to manufacturepharmaceutical emulsions. General techniques for preparation andfiltration of pharmaceutical emulsions are known at industrial scale.

In one aspect, a method of reducing the potential for an adverse eventassociated with phytonadione administration comprises: administering astable sterile composition comprising Phytonadione in its (E) isomerform that is substantially free of its (Z) isomer, at a concentration offrom about 0.1 mg/ml to about 20 mg/ml; and optionally a pH adjuster,wherein the composition has a pH of from about 3.5 to about 8.0, whereinsaid (Z) isomer is present at about 3% w/w or less of the (E) isomer;and wherein said composition is free of benzyl alcohol and comprises apolysorbate at a concentration of less than about 1:10 ratio of (E)isomer of phytonadione: polysorbate. In one aspect, the composition isadministered intramuscularly. In another aspect, the composition isadministered subcutaneously. In one specific aspect the composition isadministered at a concentration of about 2 mg/mL. In one more particularaspect, the Z-isomer is less than about 3.0% of the composition. Inanother aspect, the concentration of the E-isomer is from about 1.5 toabout 5.0 mg/mL. In another aspect, the concentration of the E-isomer isexactly or about 1.5 mg/mL; 1.6 mg/mL; 1.7 mg/mL; 1.8 mg/mL; 1.9 mg/mL;2.0 mg/mL; 2.1 mg/mL; 2.3 mg/mL; 2.5 mg/mL; 2.8 mg/mL; 3.0 mg/mL; 3.3mg/mL; 3.5 mg/mL; 4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL; 5.5 mg/mL; 6.0 mg/mL;7.0 mg/mL; 7.5 mg/mL; 8.0 mg/mL; 8.5 mg/mL; 9.0 mg/mL; 9.5 mg/mL; 10.0mg/mL; 10.5 mg/mL; 11.0 mg/mL; 12.0 mg/mL; 12.5 mg/mL; 15.0 mg/mL.

In one aspect the compositions are substantially free or free ofpreservatives, antioxidants, chelating agents. The compositions may beprepared such that the container has less than 5% of headspace oxygen.This can be accomplished by conducting the filling operation undervacuum or under an inert gas atmosphere. Techniques for such manufactureare known in the industry. Additionally, or alternatively, thecompositions may have a dissolved oxygen of less than or about 1.0 ppm.Techniques for such preparations are known in the industry.

One specific composition presented herein is a stable sterilecomposition comprising Phytonadione in its (E) isomer form that issubstantially free of its (Z) isomer, at a concentration of from about1.0 mg/mL to about 3.0 mg/mL; and optionally a pH adjuster, wherein thecomposition has a pH of from about 3.5 to about 8.0, wherein said (Z)isomer is present at about 3% w/w or less of the (E) isomer; and whereinsaid composition is free of benzyl alcohol.

EXAMPLE EMBODIMENTS

Some of the exemplary formulations of the present invention are shown inTables 1-2 as follows:

TABLE 1 Ingredients Formulation 1 Formulation 2 Formulation 3Phytonadione 2.0 mg 1.6 mg 9.0 mg E-isomer (Phytonadione)Polyoxyethylated fatty 14 mg 21 mg 60 mg acid derivative (Cremophor EL)Dextrose, 46.4 mg 46 mg 40 mg monohydrate Benzyl alcohol — — —(preservative) Hydrochloric acid/ q.s. to q.s. to q.s. to Sodiumhydroxide pH 5-7 pH 3.5-7.0 pH 3.5-7.0 Water for injection q.s. to 1 mLq.s. to 1 mL q.s. to 1 mL

TABLE 2 Ingredients Formulation 4 Formulation 5 Formulation 6Formulation 7 Phytonadione E-isomer 1.8 mg 10 mg 1.0 mg 2.0 mg(Phytonadione) Polyborbate 80 15 mg 70 mg — — Polysorbate 20 — — 8 mg 15mg Dextrose, monohydrate 32 mg 32 mg — — Sorbitol — — — 5.0% w/v Ethanol(100%) — — 2.0% v/v — Hydrochloric acid/ q.s. to q.s. to q.s. to q.s. toSodium hydroxide pH 5-7 pH 4.0-6.0 pH 3.5-7.0 pH 5-7 Water for injectionq.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL

General Procedure to Manufacture:

Important Note: Carry out all the steps in yellow light.

-   -   1. Weigh the required quantity of Polyoxyethylated fatty acid        derivative (Cremophor EL) into a beaker and warm to about 60° C.    -   2. Weigh the required quantity of Phytonadione E-isomer        (Phytonadione) and transfer into the above liquefied        Polyoxyethylated fatty acid derivative (Cremophor EL) or        Polysorbate and mix sell for about 30 minutes.    -   3. If Benzyl alcohol is present in the formulation, add the same        to the above and mix.    -   4. In a separate beaker, prepare dextrose solution by dissolving        Dextrose monohydrate in water for injection.    -   5. While mixing, slowly add the dextrose solution or Sorbitol or        Ethanol to the

Phytonadione mix and stir for about 30 minutes.

-   -   6. Check the pH of the emulsion and adjust to the required pH        with Hydrochloric acid/Sodium hydroxide. Finally, adjust the        volume of the final formulation with Water for Injection and        stir.    -   7. Filter the final formulation from 0.2 uM filter and fill        0.5/1.0 mL portions into 2 mL amber vials or 1 mL pre-filled        syringes.    -   8. Sterilize the filled containers in autoclave at 121° C. for        about 30 minutes.    -   9. Immediately after unloading the vials from the sterilizer,        shake the vials in the autoclave trays.

Methods of Administration

In one aspect, Phytonadione is administered by a caregiver such as anurse, nurse practitioner, physician, physician assistant, or anotherhealthcare personnel. The caregiver is provided with instructions by wayof a patient guide, medication guide, drug product labeling, or verbalinstructions that the Phytonadione compositions may be administered.

In one aspect, the compositions are provided to a subject in needthereof with a composition in a container that is amenable to deliverthe ready to use composition. Said container is provided in a 1 ml, 2ml, 5 ml, 10 ml, glass or plastic vial. Alternatively, aready-to-administer composition may be provided in a pre-filled syringe.Such pre-filled syringes are able to deliver drug solution volumes fromabout 0.1 ml to about 10 ml. For example, about 0.1 ml, 0.2 ml, 0.25 ml,0.3 ml, 0.4 ml, 0.5 ml, 0.75 ml, 1.0 ml, 1.25 ml, 1.5 ml, 2.0 ml, 3.0ml, 5.0 ml, 10 ml, of drug solution volume can be delivered to patients.

In all cases, the containers of said vials or pre-filled syringes may bemade of non-reacting glass, or non-reacting polymeric material such aspolypropylene or polyethylene or a mixture thereof. Several non-reactingcontainers are known in the art. The non-reacting containers describedherein include not only the vial or pre-filled syringe that makes up thebulk of the container structure, but also any other part of thecontainer that comes in contact with the drug solution, such asstoppers, plungers, etc. These also are made of non-reacting glass orpolymeric materials.

In one aspect the Phytonadione composition is administeredintramuscularly. In another aspect, the Phytonadione compositions areadministered subcutaneously or intravenously. Phytonadione is useful inthe following coagulation disorders which are due to faulty formation offactors II, VII, IX and X when caused by vitamin K deficiency orinterference with vitamin K activity:

anticoagulant-induced prothrombin deficiency caused by coumarin orindanedione derivatives;

prophylaxis and therapy of hemorrhagic disease of the newborn;

hypoprothrombinemia due to antibacterial therapy;

hypoprothrombinemia secondary to factors limiting absorption orsynthesis of vitamin K, e.g., obstructive jaundice, biliary fistula,sprue, ulcerative colitis, celiac disease, intestinal resection, cysticfibrosis of the pancreas, and regional enteritis;

other drug-induced hypoprothrombinemia where it is definitely shown thatthe result is due to interference with vitamin K metabolism, e.g.,salicylates.

Phytonadione of the present invention is useful for prophylaxis ofhemorrhagic disease of the newborn. The American Academy of Pediatricsrecommends that vitamin K1 be given to the newborn. A singleintramuscular dose of phytonadione 0.5 to 1 mg within one hour of birthis recommended.

Phytonadione of the present invention is also useful for treatment ofhemorrhagic disease of the newborn. A prompt response (shortening of theprothrombin time in 2 to 4 hours) following administration of vitamin K1is usually diagnostic of hemorrhagic disease of the newborn, and failureto respond indicates another diagnosis or coagulation disorder.(E)-isomer of phytonadione up to 1 mg should be given eithersubcutaneously or intramuscularly. Higher doses may be necessary if themother has been receiving oral anticoagulants. Whole blood or componenttherapy may be indicated if bleeding is excessive. This therapy,however, does not correct the underlying disorder and phytonadioneshould be given concurrently.

The (E)-isomer compositions of phytonadione described herein are alsouseful to treat anticoagulant-induced prothrombin deficiency in adults.To correct excessively prolonged prothrombin time caused by oralanticoagulant therapy up to 2.5 to 10 mg or up to 25 mg initially isrecommended. In rare instances up to 50 mg may be required. Frequencyand amount of subsequent doses should be determined by prothrombin timeresponse or clinical condition. If in 6 to 8 hours after parenteraladministration the prothrombin time has not been shortenedsatisfactorily, the dose should be repeated.

The (E) isomer compositions of phytonadione are useful to treathypoprothrombinemia due to other causes in adults. A dosage of 2.5 to 25mg or more (rarely up to 50 mg) recommended, the amount and route ofadministration depending upon the severity of the condition and responseobtained.

In some embodiments, a composition is administered to a subject that haspreviously had an adverse reaction to other Phytonadione compositions orthat is suspected or known to be at risk for an adverse reaction (e.g.,based on genetics, family history, etc.

Of course, it is to be understood that the above-described arrangementsare only illustrative of the application of the principles of thepresent invention. Numerous modifications and alternative arrangementsmay be devised by those skilled in the art without departing from thespirit and scope of the present invention and the appended claims areintended to cover such modifications and arrangements. Thus, while thepresent invention has been described above with particularity and detailin connection with what is presently deemed to be the most practical andpreferred embodiments of the invention, it will be apparent to those ofordinary skill in the art that numerous modifications, including, butnot limited to, variations in size, materials, shape, form, function andmanner of operation, assembly and use may be made without departing fromthe principles and concepts set forth herein.

We claim:
 1. A pharmaceutical composition comprising: Phytonadione inits (E) isomer form that is substantially free of its (Z) isomer, at aconcentration of from about 0.1 mg/ml to about 20 mg/ml; and optionallya pH adjuster, wherein the composition has a pH of from about 3.5 toabout 8.0, wherein said (Z) isomer is present at about 3% w/w or less ofthe (E) isomer; and wherein said composition is free of benzyl alcoholand, optionally, comprises a polysorbate at a concentration of less thanabout 1:10 ratio of (E) isomer of phytonadione:polysorbate.
 2. Thecomposition of claim 1, wherein the composition is substantially free orfree of preservatives, antioxidants, and chelating agents
 3. Thecomposition of claim 1, wherein said composition is in dosage form at aconcentration of 2 mg/mL.
 4. The composition of claim 3, wherein theZ-isomer is less than about 3.0% of the composition.
 5. The compositionof claim 3, wherein the E-isomer is from about 1.5 to about 5.0 mg/mL.6. The composition of claim 3, wherein the E-isomer is exactly or about1.5 mg/mL; 1.6 mg/mL; 1.7 mg/mL; 1.8 mg/mL; 1.9 mg/mL; 2.0 mg/mL; 2.1mg/mL; 2.3 mg/mL; 2.5 mg/mL; 2.8 mg/mL; 3.0 mg/mL; 3.3 mg/mL; 3.5 mg/mL;4.0 mg/mL; 4.5 mg/mL; 5.0 mg/mL; 5.5 mg/mL; 6.0 mg/mL; 7.0 mg/mL; 7.5mg/mL; 8.0 mg/mL; 8.5 mg/mL; 9.0 mg/mL; 9.5 mg/mL; 10.0 mg/mL; 10.5mg/mL; 11.0 mg/mL; 12.0 mg/mL; 12.5 mg/mL; or 15.0 mg/mL.
 7. Thecomposition of claims 1, wherein said composition is provided in anon-reacting glass or non-reacting polymeric container selected from avial container or a pre-filled syringe container.
 8. The composition ofclaim 7, wherein the container is made of polyethylene or polypropyleneor a combination thereof.
 9. The composition of claim 1, wherein saidPhytonadione in its (E) isomer form is at a concentration of from about1.0 mg/mL to about 3.0 mg/mL.
 10. The composition of claim 1, whereinsaid composition comprises said pH adjuster.
 11. The composition ofclaim 1, wherein said composition comprises said polysorbate.
 12. Amethod comprising: administering the composition of claim 1 to a mammal.13. The method of claim 12, wherein the mammal is a human.
 14. A methodof reducing the potential for anaphylactic reaction associated withphytonadione administration comprising: administering a pharmaceuticalcomposition comprising Phytonadione in its (E) isomer form that issubstantially free of its (Z) isomer, at a concentration of from about0.1 mg/ml to about 20 mg/ml; and optionally a pH adjuster, wherein thecomposition has a pH of from about 3.5 to about 8.0, wherein said (Z)isomer is present at about 3% w/w or less of the (E) isomer; and whereinsaid composition is free of benzyl alcohol and comprises a polysorbateat a concentration of less than about 1:10 ratio of (E) isomer ofphytonadione:polysorbate.
 15. The method of claim 14, wherein thecomposition is administered from a vial or a pre-filled syringe whereinthe vial or pre-filled syringe is selected from a non-reacting glass orpolymeric material.
 16. The method of claim 14, wherein the compositionis administered intramuscularly.
 17. The composition of claim 14,wherein the composition is administered subcutaneously.
 18. A method ofmanufacturing the composition of claim 7, comprising: filling saidcontainer under vacuum or under an inert gas atmosphere.
 19. The methodof claim 18, wherein said container, after filling, has less than 5% ofheadspace oxygen.
 20. The method of claim 18, wherein said compositionin said container has dissolved oxygen of less than or about 1.0 ppm.